Search

Oral mucosal melanoma (OMM) is the subject of few studies, resulting in a lack of understanding. The aim of this study is to review the current literature on OMM. The term searched was "oral mucosal melanoma" between 01/01/2000 and 03/15/2021 in the PubMed Database (MEDLINE). Patients presenting with OMM and treated in our center between January 2009 and January 2020 were included in a case series. Demographics, location, risk factors, genetic mutations, treatment performed, and overall survival (OS) rates were evaluated. The PubMed database search yielded a total of 513 results, thirty-eight articles were finally included, which amounted to 2230 cases of OMM. 13 patients were included in the case series. A male-to-female ratio of 1.28:1.00 was found with a mean age at first diagnosis of 58.2 years old. Hard palate (1060 cases) and then gingiva (794 cases) were the two main locations. No risk factors could be identified. OMM were staged III or IV at diagnosis. Mutations were described as such: KIT in 14.6% of cases, BRAF in 7%, and NRAS in 5.6%. Treatment protocols varied but radical surgery was the cornerstone treatment associated with adjuvant therapies. Immunotherapy has not been evaluated for OMM. OS rates were 43.4% at 3 years, 33.1% at 5 year and 15.4% at 10 years. OMM show distinct features from cutaneous melanoma (CM): typical locations, no identified risk factors, different mutations profile, worse prognosis with advanced stage at diagnosis. Targeted therapies are still underused compared to CM.

The first year of college may carry especially high risk for onset of alcohol use disorders. We assessed the one-year incidence of alcohol use disorders (AUD) among incoming first-year students, predictors of AUD-incidence, prediction accuracy and population impact. A prospective cohort study of first-year college students (baseline: N = 5843; response rate = 51.8%; 1-year follow-up: n = 1959; conditional response rate = 41.6%) at a large university in Belgium was conducted. AUD were evaluated with the AUDIT and baseline predictors with the Composite International Diagnostic Interview Screening Scales (CIDI-SC). The one-year incidence of AUD was 3.9% (SE = 0.4). The most important individual-level baseline predictors of AUD incidence were being male (OR = 1.53; 95% CI = 1.12-2.10), a break-up with a romantic partner (OR = 1.67; 95% CI = 1.08-2.59), hazardous drinking (OR = 3.36; 95% CI = 1.31-8.63), and alcohol use characteristics at baseline (ORs between 1.29 and 1.38). Multivariate cross-validated prediction (cross-validated AUC = 0.887) shows that 55.5% of incident AUD cases occurred among the 10% of students at highest predicted risk (20.1% predicted incidence in this highest-risk subgroup). Four out of five students with incident AUD would hypothetically be preventable if baseline hazardous drinking was to be eliminated along with a reduction of one standard deviation in alcohol use characteristics scores, and another 15.0% would potentially be preventable if all 12-month stressful events were eliminated. Screening at college entrance is a promising strategy to identify students at risk of transitioning to more problematic drinking and AUD, thus improving the development and deployment of targeted preventive interventions. ispartof: European Child & Adolescent Psychiatry vol:31 issue:7 ispartof: location:Germany status: Published online

BackgroundThe COVID-19 pandemic has had a major impact on the mental health of healthcare workers, yet studies in primary care workers are scarce.AimTo investigate the prevalence of and associated factors for psychological distress in primary care workers during the first COVID-19 outbreak.Design and settingThis was a multicentre, cross-sectional, web-based survey conducted in primary healthcare workers in Spain, between May and September 2020.MethodHealthcare workers were invited to complete a survey to evaluate sociodemographic and work-related characteristics, COVID-19 infection status, exposure to patients with COVID-19, and resilience (using the Connor–Davidson Resilience Scale), in addition to being screened for common mental disorders (depression, anxiety disorders, post-traumatic stress disorder, panic attacks, and substance use disorder). Positive screening for any of these disorders was analysed globally using the term ‘any current mental disorder’.ResultsA total of 2928 primary care professionals participated in the survey. Of them, 43.7% (95% confidence interval [CI] = 41.9 to 45.4) tested positive for a current mental disorder. Female sex (odds ratio [OR] 1.61, 95% CI = 1.25 to 2.06), having previous mental disorders (OR 2.58, 95% CI = 2.15 to 3.10), greater occupational exposure to patients with COVID-19 (OR 2.63, 95% CI = 1.98 to 3.51), having children or dependents (OR 1.35, 95% CI = 1.04 to 1.76 and OR 1.59, 95% CI = 1.20 to 2.11, respectively), or having an administrative job (OR 2.24, 95% CI = 1.66 to 3.03) were associated with a higher risk of any current mental disorder. Personal resilience was shown to be a protective factor.ConclusionAlmost half of primary care workers showed significant psychological distress. Strategies to support the mental health of primary care workers are necessary, including designing psychological support and resilience-building interventions based on risk factors identified.

International audience; Aim: To describe real-world pembrolizumab administration and outcomes for advanced melanoma in France. Materials & methods: Using the MelBase longitudinal database, this multicenter historical-prospective study examined treatment and outcomes of patients with nonuveal, unresectable stage III/IV melanoma initiating pembrolizumab from April 2016 to September 2017, with follow-up to September 2019. Kaplan–Meier time-to-event analyses were conducted. Results: Of 223 patients (median age 67; 51% men), 134 (60%), 36 (16%) and 53 (24%) initiated pembrolizumab in first-, second- and third-line, respectively. Median overall survival (months) was 32.6 (95% CI: 20.3–not reached [NR]), 14.4 (8.6–NR) and 9.3 (6.4–NR), respectively. Best real-world tumor response of complete or partial response was recorded for 49, 39 and 26% of patients, respectively. Conclusion: Study results support benefits of pembrolizumab therapy for advanced melanoma.

BackgroundAchondroplasia is the most common form of skeletal dysplasia, with serious comorbidities and complications that may occur from early infancy to adulthood, requiring lifelong management from a multidisciplinary team expert in the condition The European Achondroplasia Forum guiding principles of management highlight the importance of accurate diagnosis and timely referral to a centre specialised in the management of achondroplasia to fully support individuals with achondroplasia and their families, and to appropriately plan management. The European Achondroplasia Forum undertook an exploratory audit of its Steering Committee to ascertain the current situation in Europe and to understand the potential barriers to timely diagnosis and referral.ResultsDiagnosis of achondroplasia was primarily confirmed prenatally (66.6%), at Day 0 (12.8%) or within one month after birth (12.8%). For suspected and confirmed cases of achondroplasia, a greater proportion were identified earlier in the prenatal period (87.1%) with fewer diagnoses at Day 0 (5.1%) or within the first month of life (2.6%). Referral to a specialist centre took place after birth (86.6%), predominantly within the first month, although there was a wide variety in the timepoint of referral between countries and in the time lapsed between suspicion or confirmed diagnosis of achondroplasia and referral to a specialist centre.ConclusionsThe European Achondroplasia Forum guiding principles of management recommend diagnosis of achondroplasia as early as possible. If concerns are raised at routine ultrasound, second line investigation should be implemented so that the diagnosis can be reached as soon as possible for ongoing management. Clinical and radiological examination supported by molecular testing is the most effective way to confirm diagnosis of achondroplasia after birth. Referral to a centre specialised in achondroplasia care should be made as soon as possible on suspicion or confirmation of diagnosis. In countries or regions where there are no official skeletal dysplasia reference or specialist centres, priority should be given to their creation or recognition, together with incentives to improve the structure of the existing multidisciplinary team managing achondroplasia. The length of delay between diagnosis of achondroplasia and referral to a specialist centre warrants further research.

Research is scarce on the prospective predictors of first onset suicidal thoughts and behaviors (STB) and the accuracy of these predictors in university students, particularly in low-and-middle income countries. Therefore, we assessed the 1-year incidence of STB among first-year students, a broad range of prospective predictors of STB incidence, and evaluated the prediction accuracy of a baseline multivariate risk prediction model to identify students at highest risk for STB onset over the subsequent 12 months.Students (n = 3238) from 13 universities in Mexico completed an online survey developed for the World Mental Health International College Student Surveys in their first year and again 12 months after. We ran generalized linear models and receiver operator curves.The 1-year incidence of suicidal ideation, plan and attempt was 8.53%, 3.75%, and 1.16%, respectively. Predictors in final models were female sex (ideation only), minority sexual orientation (ideation only), depression, eating disorders, ADHD (ideation and plan), ongoing arguments or breakup with a romantic partner (ideation only), emotional abuse (ideation only), parental death (ideation, plan), not Catholic/Christian (ideation, plan), not having someone to rely on, psychotic experiences (plan only), and insufficient sleep (attempt only). Prediction accuracy for ideation, plan and attempt was area under the curve = 0.76, 0.81 and 0.78, respectively. Targeting the top 10% of students at highest risk could reduce STB in the subsequent year up to 36%.By assessing these risk/protective factors in incoming students we identified students at greatest risk for developing STB to whom suicide prevention strategies could be targeted.

International audience; Background: Significant progress was recently observed in the treatment of metastatic melanoma (MM). With >50% of patients now reaching a second line of treatment and a significant improvement in the survival rate, an assessment of quality of life (QoL) during the whole course of the disease becomes necessary. The objective of this study was to describe the QoL of patients with MM in France, from their diagnosis of advanced disease to their death, in real life. Methods: QoL data were collected through MelBase, a prospective, French, multicentric cohort dedicated to the follow-up of adults with MM. QoL was assessed using the EuroQoL-5D questionnaire and the Functional Assessment of Cancer Treatment (FACT)-Melanoma questionnaire at the time of study inclusion, every 3 months, and at the time of each treatment change until death. To assess longitudinal changes from baseline to death, mixed-effect models for repeated-measures analyses were used to control for baseline covariates. Results: QoL was assessed in 1435 patients who were included in the study between 2013 and 2018. The median follow-up was 9.4 months, and 47% of patients died during follow-up. During first-line treatment, the model-based, mean utility score was 0.830 (95% CI, 0.818-0.843), the mean FACT-General score was 77.22 (95% CI, 76.23-78.22), and the mean FACT-Melanoma score was 129.46 (95% CI, 128.02-130.90). At the time of a change in treatment line, there was a decrease of −0.027 (95% CI, −0.03, −0.02) in the utility score, −1.82 (95% CI, −1.88, −1.76) in the FACT-General score, and −2.98 (95% CI, −3.05, −2.91) in the FACT-Melanoma score compared with first-line treatment. Conclusions: In the MelBase cohort, the QoL among patients with MM seems to be fairly stable over the whole disease course, although a small but significant decrease at time therapy is changed is observed.

Mental health disparities have been documented among sexual minority college students, but there is a dearth of evidence from developing countries. The aim is to estimate the prevalence of 12-month mental and substance use disorders across a range of sexual identities among first-year college students in Mexican universities, and test whether there is an association between sexual identity and disorders and whether the association is moderated by gender. The University Project for Healthy Students, a web-based survey conducted as part of the World Health Organization’s World Mental Health International College Student initiative, recruited 7874 students from nine Mexican universities in 2016 and 2017. Logistic regressions estimated the association of sexual identity with 12-month major depressive episode, generalized anxiety disorder, panic disorder, alcohol abuse/dependence, and drug abuse/dependence, with interaction terms for gender. Compared to heterosexual students reporting no same-sex attraction (SSA), heterosexual students with SSA (AORs range 1.77–3.67) and lesbian/gay and bisexual students (AORs range 2.22–5.32) were at a higher risk for several disorders. Asexual students were at higher risk for drug abuse/dependence (AOR = 3.64). Students unsure of their sexual identity were at a higher risk for major depressive episode, panic disorder, and drug abuse/dependence (AORs range 2.25–3.82). Gender differences varied across sexual identity and disorder. These findings are the first empirical report of sexual minority psychiatric disparities among a college student population from a developing nation and underscore the importance of clinical interventions that address mental health needs among sexual minority college students.

International audience; Background: Targeted therapies such as BRAF and MEK inhibitors and immunotherapies have been made available to treat melanoma.Objectives: To provide an overview of the management of the French Stage III melanoma population after complete lymph node resection prior to new adjuvant therapies.Materials and methods: A subgroup data analysis.Results: Data from 1,835 patients were analysed (15.58% Stage IIIA, 39.24% Stage IIIB, 43.92% Stage IIIC and 1.25% Stage IIID). Superficial spreading melanoma was the most frequent (70.98% in Stage IIIA for whom mutation analysis was performed; BRAF mutation was identified in up to 62% Stage IIIA patients). Sentinel lymph node biopsy was performed in 88.46% of Stage IIIA patients, 42.36% of Stage IIIB, 53.97% of Stage IIIC and 34.78% of Stage IIID. Up to 80% of Stage IIIA patients had no adjuvant treatment follow-up. Ulceration (p = 0.004; RR: 2.98; 95% CI: 1.4-6.3) and age at diagnosis (p = 0.0002; RR: 1.04; 95% CI: 1.02-1.06) were significant predictive factors for survival. Adjuvant interferon-α was administered in up to 13.04% of Stage IIID patients.Conclusion: Only a small number of Stage III melanoma patients were treated with interferon-α in adjuvant settings. New adjuvant therapies are currently having an effect on clinical practice in France, increasing survival and decreasing cost.

BackgroundThe Leuven Affect and Pleasure Scale (LAPS) was developed as an outcome measure in major depressive disorder (MDD) tha treflects patient treatment expectations. The present report investigates whether the LAPS negative affect, the LAPS positive affect, and the LAPS hedonic tone have added value on top of the Hamilton Depression Rating Scale (HAMD) in explaining generic as well as patient-centered outcomes.MethodsA total of 109 outpatients with Diagnostic and Statistical Manual of Mental Disorders, fifth edition, criteria for MDD were assessed over 8 weeks of antidepressant treatment. At baseline and after 2, 4, and 8 weeks, the LAPS, HAMD, Snaith–Hamilton Pleasure Scale (SHAPS), Positive and Negative Affect Scale (PANAS), and Sheehan Disability Scale were administered. The Clinical Global Impression of Improvement (CGI-I) and the Patient Global Impression of Improvement (PGI-I) were also administered at endpoint.ResultsChanges in LAPS negative affect, LAPS positive affect, and LAPS hedonic tone explain 14% of the additional variance in CGI-I, 21% in PGI-I, 37% in cognitive functioning, 32% in overall functioning, 31% in “my life is meaningful,” and 45% in “I feel happy.” Compared to standard scales (PANAS and SHAPS), the LAPS negative affect, LAPS positive affect, and LAPS hedonic tone differentiate better between different levels of CGI-I or PGI-I.ConclusionsThe LAPS has added value (on top of the HAMD) in explaining changes in both generic outcomes (CGI-I/PGI-I) and patient-centered dimensions. The LAPS negative and positive affects and the LAPS hedonic tone differentiate CGI-I and PGI-I scores better than corresponding scales supposed to cover the same domains.

Background Suicide prevention is an emerging priority for public health systems. Here, we present the Catalonia Suicide Risk Code (CSRC), a secondary suicide prevention program that provides a systematic approach to follow-up care for patients at risk. We describe the care pathway of the CSRC and characteristics of the patients enrolled in the program. Methods Observational study based on data extracted from the Catalan health care system between the years 2014 and 2019. The following patient-related data were obtained: sociodemographic and clinical characteristics, characteristics of suicidal behaviour, and pathway of care. Results A total of 12,596 individuals (64.1% women) were screened for suicide risk and 8,403 (66.7%) were subsequently enrolled in the CSRC. Adherence data show that most patients (81.9%) attended a face-to-face appointment and most (67.1%) were successfully contacted by telephone afterwards. Most face-to-face appointments were performed within 10 days of enrolment for adults and 72 h for minors. Psychiatric disorders were significant risk factors for both men and women. Females were significantly more likely to report stressful life events, while males were more likely to report social problems. Compared to men, women were more likely to use poisoning. Limitations Adherence to the CSRC care pathway might reflect obstacles to its implementation. Due to the observational study design, it is not possible to determine the effectiveness of the CSRC to reduce suicide re-attempts. Conclusions Although the CSRC successfully provided follow-up care for many individuals at high risk of suicide, greater adherence to the CSRC care pathway is needed.

Background: Binge eating and purging behaviors (BPB) are common among college students, but evidence is scant on prevalence and associations of BPB with mental health problems and objective academic performance. This study aims to investigate: (a) 12-month prevalence of BPB among college first-year students, (b) comorbidity patterns of BPB with various mental health problems, and (c) the association of BPB with objective academic functioning. Methods: Using data from the Leuven College Surveys (Belgium), as part of the World Mental Health Surveys International College Student initiative, we cross-sectionally assessed 12-month BPB and mental health problems among college first-year students (n = 4,889; response rate = 73.2%) at the beginning of the academic year. Objective measures of academic functioning (final grades, expressed in academic year percentage “AYP” [0–100%] and academic failure) were obtained from administrative records at the end of the academic year. Results: Twelve-month prevalence of BPB was 7.6% (7.3%binge eating and 1.0%purging), with higher rates among females than males. Bivariate models showed an association between BPB and numerous mental health problems (ORs = 3.4–18.4). Multivariate models showed associations with non-suicidal self-injury, post-traumatic stress, internalizing/externalizing problems and suicidal ideation. After controlling for sociodemographic characteristics and comorbid mental health problems, BPB were still associated with lower AYP (−4.1 to −11.2% range) and elevated odds of academic year failure (ORs = 1.4–4.2). Conclusions: BPB (especially binge eating) are relatively common and associated with mental health problems, comparatively low academic performance, and higher risk of academic failure among college first-year students. Further study is needed to examine the causal dynamics underlying these associations.

The type of pre-existing disorder might determine changes in mental health symptoms (i.e., anxiety, depression) during the COVID-19 pandemic and influence the effect of psychological factors (e.g., social support, resilience, stress) on such symptoms.Longitudinal data from two assessments (June-2020 and February/March-2021) collected through telephone interviews (Spanish general population) were analysed. Outcome variables included anxiety (GAD-7) and depressive symptoms (PHQ-8). Psychological factors included COVID-perceived stress (adapted COVID-perceived risk scale), social support (OSSS-3), and resilience (CD-RISC). Pre-existing mental conditions (3 groups: mood, anxiety, and comorbid depression+anxiety) were assessed using the CIDI checklist. Changes in anxiety and depressive symptoms between baseline and follow-up were assessed with the paired samples Wilcoxon test. Tobit regression and interaction models were conducted to test associations between psychological factors and these symptoms in follow-up.Final sample included 1942 participants (mean age 49.6 yrs., ±16.7; 51.7 % females). Anxiety symptoms increased in all groups except for those with pre-existing mood conditions. Depressive symptoms only increased in those without pre-existing mental disorders and in those with pre-existing anxiety. Higher baseline resilience, increases in social support, and decreases in COVID-perceived stress were associated with lower anxiety and depressive symptoms. The type of pre-existing mental disorder did not modify these associations.Lack of pre-pandemic data and the limited number of pre-existing mental conditions.Having pre-pandemic mental disorders is associated with different patterns of anxiety and depressive symptoms during the pandemic. COVID-related stress, social support, and resilience are key factors in improving mental health regardless of the mental diagnosis.

On January 2020, the French College of Gynecologists and Obstetricians (CNGOF) issued new Clinical Practice Guidelines (CPG) "Breech Presentation". Since then, it is recommended to use a tocolytic agent to improve the success rate of External Cephalic Version (ECV). The aim of this study, one year after these CPG, is to compare ECV without (before CPG) and with (after CPG) tocolysis in a type III maternity hospital. We intend to assess its effects on immediate success rate of ECV and obstetrical and neonatal outcomes.This is a single-center retrospective study conducted in Nantes University Hospital. We collected patient characteristics, immediate success rate, and maternal and neonatal outcomes at delivery of all ECV over two periods: the first one during 2019 (before CPG) and the second one from June 2020 to June 2021 (after CPG).We included 253 patients: 126 in the first period and 127 in the second period. Immediate success rate of ECV was significantly higher since the use of tocolysis: 38.6 % (period 2) vs 23.8 % (period 1) (P=0.011). However, there was not significant difference found for cephalic presentation at birth, mode of delivery or obstetrical and neonatal outcomes.The immediate success rate is significantly improved with the widespread use of tocolysis during ECV, with no change in obstetrical and neonatal outcomes.

Comment in Does HIV-1 virulence matter in the ART era? Lewitus E, Rolland M. Med (N Y). 2022 Apr 8;3(4):217-219. doi: 10.1016/j.medj.2022.03.003. PMID: 35590149; International audience; We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log 10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.

Background: Depression and anxiety are both prevalent among university students. They frequently co-occur and share risk factors. Yet few studies have focused on identifying students at highest risk of first-onset and persistence of either of these conditions. Methods: Multicenter cohort study among Spanish first-year university students. At baseline, students were assessed for lifetime and 12-month Major Depressive Episode and/or Generalized Anxiety Disorder (MDE-GAD), other mental disorders, childhood-adolescent adversities, stressful life events, social support, socio-demographics, and psychological factors using web-based surveys; 12-month MDE-GAD was again assessed at 12-month follow-up. Results: A total of 1253 students participated in both surveys (59.2% of baseline respondents; mean age = 18.7 (SD = 1.3); 56.0% female). First-onset of MDE-GAD at follow-up was 13.3%. Also 46.7% of those with baseline MDE-GAD showed persistence at follow-up. Childhood/Adolescence emotional abuse or neglect (OR= 4.33), prior bipolar spectrum disorder (OR= 4.34), prior suicidal ideation (OR=4.85) and prior lifetime symptoms of MDE (ORs=2.33-3.63) and GAD (ORs=2.15-3.75) were strongest predictors of first-onset MDE-GAD. Prior suicidal ideation (OR=3.17) and prior lifetime GAD symptoms (ORs=2.38-4.02) were strongest predictors of MDE-GAD persistence. Multivariable predictions from baseline showed AUCs of 0.76 for first-onset and 0.81 for persistence. 74.9% of first-onset MDE-GAD cases occurred among 30% students with highest predicted risk at baseline. Limitations: Self-report data were used; external validation of the multivariable prediction models is needed. Conclusion: MDE-GAD among university students is frequent, suggesting the need to implement web-based screening at university entrance that identify those students with highest risk.

Introduction Health-care organizations are facing a high burden of ergonomic occupational accidents, and prevention is a continuous point of interest. In this manuscript, we describe the characteristics of ergonomic accidents in a large Belgian university hospital and discuss the value of near misses. Methods Combining databases, we identified the frequency [number of accidents x 10(6) hours worked per year], severity (number of days off work x 10(3) hours worked per year), and profile of the victims of occupational ergonomic accidents (with absence from work) or incidents or near-misses (without absence from work). Ergonomic accidents and incidents include slips, trips, falls, injurious body movements, overexertion, and handling heavy weights. Results In a period of 23 years, we noticed a significant decrease in the frequency of ergonomic accidents (from about 7 to about 4 standard units), without changes in the severity. The decrease in the frequency of accidents is mirrored by an increase in the frequency of incidents (from about 4 to about 6 standard units). Female and older employees are more vulnerable to accidents, and the frequency was between two and four times higher for employees mostly involved in manual tasks compared to employees mostly involved in managerial tasks. The profile of the victims and the causes of accidents and incidents were identical. Conclusion Although it is premature to assume a cause-consequence relationship between incidents and accidents, it is tempting to speculate that the increased ratio of the frequencies of incidents over accidents might be one of the variables reflecting the adequacy of preventive measures and the growth of safety behavior.

Incidence rates of Merkel cell carcinoma (MCC), an uncommon skin cancer with an aggressive disease course, have increased in recent decades. Limited treatment options are available for patients with metastatic MCC (mMCC). Avelumab, an anti-programmed cell death-ligand 1 monoclonal antibody, became the first approved treatment for mMCC after the results of the phase 2 JAVELIN Merkel 200 study. Prior to its regulatory approval, an expanded access program (EAP) enabled compassionate use of avelumab in patients with mMCC. Here we report findings from patients enrolled in the EAP in Europe and the Middle East. Efficacy and safety data were provided at the discretion of treating physicians. Between March 2, 2016, and December 22, 2018, 403 requests for avelumab were received from 21 countries, and avelumab was supplied to 335 patients. Most patients (96.7%) received avelumab as second-line or later treatment. In 150 patients for whom response data were available, the objective response rate was 48.0%, and in responding patients, median duration of treatment was 7.4 months (range, 1.0-41.7 months). The most common treatment-related adverse events were infusion-related reaction (2.4%) and pyrexia (2.1%), and no new safety signals were observed. Overall, results from European and Middle Eastern patients enrolled in this EAP confirm the efficacy and safety of avelumab treatment observed in previous studies in patients with mMCC. ispartof: INTERNATIONAL JOURNAL OF CANCER vol:149 issue:11 pages:1926-1934 ispartof: location:United States status: published

Purpose In a significant proportion of children born small for gestational age (SGA) with failure of catch-up growth, the etiology of short stature remains unclear after routine diagnostic workup. We wanted to investigate if extensive analysis of the (epi)genome can unravel the cause of growth failure in a significant portion of these children. Patients and Methods Twenty SGA children treated with GH because of short stature were selected from the BELGROW database of the Belgian Society for Pediatric Endocrinology and Diabetology for exome sequencing, single-nucleotide polymorphism (SNP) array and genome-wide methylation analysis to identify the (epi)genetic cause. First-year response to GH was compared with the response of SGA patients in the KIGS database. Results We identified (likely) pathogenic variants in 4 children (from 3 families) using exome sequencing and found pathogenic copy number variants in 2 probands using SNP array. In a child harboring a NSD1-containing microduplication, we identified a DNA methylation signature that is opposite to the genome-wide DNA methylation signature of Sotos syndrome. Moreover, we observed multilocus imprinting disturbances in 2 children in whom no other genomic alteration could be identified. Five of 6 children with a genetic diagnosis had an “above average” response to GH. Conclusions The study indicates that a more advanced approach with deep genotyping can unravel unexpected (epi)genomic alterations in SGA children with persistent growth failure. Most SGA children with a genetic diagnosis had a good response to GH treatment.

Background: Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. Methods: We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients. Results: Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types. Conclusion: Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients., SCOPUS: ar.j, info:eu-repo/semantics/published

Colonic torsion is a life-threatening condition that results in colonic ischemia, necrosis, perforation, sepsis, and eventual death. The aim of this multicenter, retrospective case series study was to describe the CT findings in dogs with surgically confirmed colonic torsion. Medical records were searched for dogs with surgically confirmed colonic torsion following abdominal CT. Five dogs met the inclusion criteria. Three had a history of chronic intermittent diarrhea prior to presentation. Two dogs presented with acute vomiting, diarrhea, and abdominal pain and one dog presented with acute vomiting and lethargy. Computed tomographic findings in all dogs with surgically confirmed colonic torsion include: "whirl sign," displacement and distension of the cecum and colon, focal narrowing of the colon, and distension of the mesenteric vasculature in all dogs (5/5); streaky peritoneal fat and peritoneal effusion (4/5), pneumatosis coli (2/5), small intestinal distension (2/5), portal vein thrombosis (1/5), and reduced colonic wall contrast enhancement (1/5). In all dogs (5/5), the torsion site was the descending colon and demonstrated an anticlockwise rotation. At surgery, three of the five dogs had a partial colonic torsion with hyperemia at the site of obstruction and two of the five dogs had a complete torsion with marked necrosis of the colonic wall. Displacement of the colon and cecum, segmental distension and focal narrowing of the colon, the presence of a "whirl sign" and distension of the mesenteric vasculature are CT findings highly suggestive of colonic torsion.

AIM: To assess gender differences in the association between risk/protective factors and suicidal thoughts and behaviors (STB); and whether there is any gender-interaction with those factors and STB; among Spanish university students. METHODS: data from baseline online survey of UNIVERSAL project, a multicenter, observational study of first-year Spanish university students (18-24 years). We assessed STB; lifetime and 12-month negative life-events and family adversities; mental disorders; personal and community factors. Gender-specific regression models and gender-interactions were also analyzed. RESULTS: We included 2,105 students, 55.4% women. Twelve-month prevalence of suicidal ideation (SI) was 10%, plans 5.7%, attempts 0.6%. Statistically significant gender-interactions were found for lifetime anxiety disorder, hopelessness, violence between parents, chronic health conditions and family support. Lifetime mood disorder was a common risk factor of SI for both genders (Females: OR= 5.5; 95%CI 3.3-9.3; Males: OR= 4.4; 95%CI 2.0-9.7). For females, exposure to violence between parents (OR= 3.5; 95%CI 1.7-7.2), anxiety disorder (OR= 2.7; 95%CI 1.6-4.6), and alcohol/substance disorder (OR= 2.1; 95%CI 1.1-4.3); and for males, physical childhood maltreatment (OR= 3.6; 95%CI 1.4-9.2), deceased parents (OR= 4.6; 95%CI 1.2-17.7), and hopelessness (OR= 7.7; 95%CI 2.8-21.2), increased SI risk. Family support (OR= 0.5; 95%CI 0.2-0.9) and peers/others support (OR= 0.4; 95%CI 0.2-0.8) were associated to a lower SI risk only among females. CONCLUSIONS: Only mood disorder was a common risk factor of SI for both genders, whereas important gender-differences were observed regarding the other factors assessed. The protective effect from family and peers/others support was observed only among females. Further research assessing underlying mechanisms and pathways of gender-differences is needed. info:eu-repo/semantics/acceptedVersion

Valve size selection for transcatheter aortic valve replacement (TAVR) is currently based on cardiac CT-scan. At variance with patient-specific computer simulation, this does not allow the assessment of the valve-host interaction. We aimed to compare clinical valve size selection and valve size selection by an independent expert for computer simulation. A multicenter retrospective analysis of valve size selection by the physician and the independent expert in 141 patients who underwent TAVR with the self-expanding CoreValve or Evolut R. Baseline CT-scan was used for clinical valve size selection and for patient-specific computer simulation. Simulation results were not available for clinical use. Overall true concordance between clinical and simulated valve size selection was observed in 47 patients (33%), true discordance in 15 (11%) and ambiguity in 79 (56%). In 62 (44%, cohort A) one valve size was simulated whereas two valve sizes were simulated in 79 (56%, cohort B). In cohort A, concordance was 76% and discordance was 24%; a smaller valve size was selected for simulation in 10 patients and a larger in 5. In cohort B, a different valve size was selected for simulation in all patients in addition to the valve size that was used for TAVR. The different valve size concerned a smaller valve in 45 patients (57%) and a larger in 34 (43%). Selection of the valve size differs between the physician and the independent computer simulation expert who used the same source of information. These findings indicate that valve sizing in TAVR is still more intricate than generally assumed.

Cartilage hair hypoplasia (CHH), anauxetic dysplasia 1, and anauxetic dysplasia 2 are rare metaphyseal dysplasias caused by biallelic pathogenic variants in RMRP and POP1, which encode the components of RNAse-MRP endoribonuclease complex (RMRP) in ribosomal biogenesis pathway. Nucleolus and neural progenitor protein (NEPRO), encoded by NEPRO (C3orf17), is known to interact with multiple protein subunits of RMRP. We ascertained a 6-year-old girl with skeletal dysplasia and some features of CHH. RMRP and POP1 did not harbor any causative variant in the proband. Parents-child trio exomes revealed a candidate biallelic variant, c.435G>C, p.(Leu145Phe) in NEPRO. Two families with four affected individuals with skeletal dysplasia and a homozygous missense variant, c.280C>T, p.(Arg94Cys) in NEPRO, were identified from literature and their published phenotype was compared in detail to the phenotype of the child we described. All the five affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. Protein modeling and stability prediction showed that the mutant protein has decreased stability. Both the reported variants are in the same domain of the protein. Our report delineates the clinical and radiological characteristics of an emerging ribosomopathy caused by biallelic variants in NEPRO.

This study proposes a new framework to optimize the design of a transcatheter aortic valve through patient-specific finite element and fluid dynamics simulation. Two geometrical parameters of the frame, the diameter at ventricular inflow and the height of the first row of cells, were examined using the central composite design. The effect of those parameters on postoperative complications was investigated by response surface methodology, and a Nonlinear Programming by Quadratic Lagrangian algorithm was used in the optimization. Optimal and initial devices were then compared in 12 patients. The comparison was made in terms of device performance [i.e., reduced contact pressure on the atrioventricular conduction system and paravalvular aortic regurgitation (AR)]. Results suggest that large diameters and high cells favor higher anchoring of the device within the aortic root reducing the contact pressure and favor a better apposition of the device to the aortic root preventing AR. Compared to the initial device, the optimal device resulted in almost threefold lower predicted contact pressure and limited AR in all patients. In conclusion, patient-specific modelling and simulation could help to evaluate device performance prior to the actual first-in-human clinical study and, combined with device optimization, could help to develop better devices in a shorter period.

OBJECTIVES: Mental disorders and suicidal thoughts and behaviors (STB) are common and burdensome among college students. Although available evidence suggests that only a small proportion of the students with these conditions receive treatment, broad-based data on patterns of treatment are lacking. The aim of this study is to examine the receipt of mental health treatment among college students cross-nationally. METHODS: Web-based self-report surveys were obtained from 13,984 first year students from 19 colleges in eight countries across the world as part of the World Health Organization's World Mental Health-International College Student Initiative. The survey assessed lifetime and 12-month common mental disorders/STB and treatment of these conditions. RESULTS: Lifetime and 12-month treatment rates were very low, with estimates of 25.3-36.3% for mental disorders and 29.5-36.1% for STB. Treatment was positively associated with STB severity. However, even among severe cases, lifetime and 12-month treatment rates were never higher than 60.0% and 45.1%, respectively. CONCLUSIONS: High unmet need for treatment of mental disorders and STB exists among college students. In order to resolve the problem of high unmet need, a reallocation of resources may focus on innovative, low-threshold, inexpensive, and scalable interventions. ispartof: INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH vol:28 issue:2 ispartof: location:United States status: published

Objectives: Comorbidity is a common feature of mental disorders. However, needs assessment surveys focus largely on individual disorders rather than on comorbidity even though the latter is more important for predicting suicidal thoughts and behaviors. In the current report, we take a step beyond this conventional approach by presenting data on the prevalence and correlates (sociodemographic factors, college-related factors, and suicidal thoughts and behaviors) of the main multivariate profiles of common comorbid Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV disorders among students participating in the first phase of the World Health Organization World Mental Health International College Student initiative. Method: A web-based mental health survey was administered to first year students in 19 colleges across eight countries (Australia, Belgium, Germany, Mexico, Northern Ireland, South Africa, Spain, United States; 45.5% pooled response rate) to screen for seven common DSM-IV mental disorders: major depression, mania/hypomania, generalized anxiety disorder, panic disorder, attention-deficit/hyperactivity disorder, alcohol use disorder, and drug use disorder. We focus on the 14,348 respondents who provided complete data; 38.4% screened positive for at least one 12-month disorder. Results: Multivariate disorder profiles were detected using latent class analysis (LCA). The least common class (C1; 1.9% of students) was made up of students with high comorbidity (four or more disorders, the majority including mania/hypomania). The remaining 12-month cases had profiles of internalizing–externalizing comorbidity (C2; 5.8%), internalizing comorbidity (C3; 14.6%), and pure disorders (C4; 16.1%). The 1.9% of students in C1 had much higher prevalence of suicidal thoughts and behaviors than other students. Specifically, 15.4% of students in C1 made a suicide attempt in the 12 months before the survey compared with 1.3–2.6% of students with disorders in C2–4, 0.2% of students with lifetime disorders but no 12-month disorders (C5), and 0.1% of students with no lifetime disorders (C6). Conclusions: In line with prior research, comorbid mental disorders were common; however, sociodemographic correlates of LCA profiles were modest. The high level of comorbidity underscores the need to develop and test transdiagnostic approaches for treatment in college students.

Osteogenesis imperfecta (OI) is the commonest form of heritable bone fragility. It is mainly characterized by fractures, hearing loss and dentinogenesis imperfecta. OI patients are at increased risk of cardiovascular disease of variable severity. Aortic aneurysm/dissection is one of the rarer but potentially serious cardiovascular complications of OI. So far, only six patients with aortic dissection and OI have been reported. As such, present OI diagnostic guidelines do not recommend systematic screening of patients for aortopathy. Here, we report on the clinical and molecular characteristics of three new OI patients and one additional patient with a first degree relative who presented with aortic dissection and/or aneurysm surgery. This observation further opens up the discussion on the need for and extent of cardiovascular screening in adult patients with OI.

Background/purpose Photodynamic therapy (PDT) is an established treatment for actinic keratosis (AK). Among the approved protocols in Europe, the most widely used involves irradiation with the Aktilite CL 128 (C-PDT). We aimed to assess the heterogeneity of irradiance over the treatment area when using C-PDT. We also investigated whether there is a cut-off value for protoporphyrin IX (PpIX)-weighted irradiance that may predict the treatment outcome of C-PDT. Methods An Ophir PD300 photodiode sensor connected to an Ophir Laser Star power meter was used to measure the irradiance delivered to 114 AKs of the scalp and forehead of 19 patients treated with C-PDT. The PpIX-weighted irradiances were deduced and cross-referenced with the complete responses at 3 months. Results From the measured irradiances ranging from 0.25 to 60 mW/cm2 (average: 31.94 mW/cm2 ), a standard deviation of 17.17 mW/cm2 was computed. Irradiance heterogeneity over the treatment area during C-PDT was demonstrated. The 66/114 AKs with a complete response at 3 months (57.89%) received a mean PpIX-weighted irradiance of 0.52 mW/cm2 vs 0.56 mW/cm2 for the resistant 48/114 AKs (42.11%). No significant effect of PpIX-weighted irradiance on the complete response at 3 months was found (odds ratio for a 0.1-unit change, 0.96; 95% confidence interval, 0.83 to 1.10; P = 0.53). Therefore, no cut-off value for PpIX-weighted irradiance that predicts treatment outcome could be identified. Conclusions A device enabling homogeneous irradiation at a lower irradiance than the Aktilite CL 128 may therefore be suitable. This lower irradiance may further increase the treatment tolerance by patients.

Obsessive-compulsive symptom dimensions are important in studies about the pathogenesis and treatment of obsessive-compulsive disorder. More than 30 factor analytic studies using the Yale-Brown Obsessive Compulsive Scale Symptom Checklist (Y-BOCS-SC) interview version have been published. However, a drawback of the Y-BOCS-SC interview is that it is time-consuming for the clinician. Baer's self-report version of the Y-BOCS-SC could be a less time-consuming alternative. The purpose of this study was to examine the factor structure of Baer's self-report Y-BOCS-SC. In a sample of 286 patients, we performed two factor analyses, one using categories and one using items of the Y-BOCS-SC. Using category-level data, we identified four factors; when using items we identified six factors. Symptom dimensions for contamination/cleaning, symmetry/repeating/counting/ordering and hoarding were found in both analyses. The impulsive aggression, pathological doubt, sexual, religious somatic and checking categories formed one factor in the analysis using category-level data and divided into three factors using item-level data. These factors correspond with studies using the interview version and support our hypothesis that the self-report version of the Y-BOCS-SC could be an alternative for the interview version.

0, Brussels Collaboration on Bodily Integrity, info:eu-repo/semantics/published

Aims: To investigate the prevalence of suicidal thoughts and behaviours (STB; i.e. suicidal ideation, plans or attempts) in the Spanish adult general population during the first wave of the Spain coronavirus disease 2019 (COVID-19) pandemic (March-July, 2020), and to investigate the individual- and population-level impact of relevant distal and proximal STB risk factor domains. Methods: Cross-sectional study design using data from the baseline assessment of an observational cohort study (MIND/COVID project). A nationally representative sample of 3500 non-institutionalised Spanish adults (51.5% female; mean age = 49.6 [s.d. = 17.0]) was taken using dual-frame random digit dialing, stratified for age, sex and geographical area. Professional interviewers carried out computer-assisted telephone interviews (1-30 June 2020). Thirty-day STB was assessed using modified items from the Columbia Suicide Severity Rating Scale. Distal (i.e. pre-pandemic) risk factors included sociodemographic variables, number of physical health conditions and pre-pandemic lifetime mental disorders; proximal (i.e. pandemic) risk factors included current mental disorders and a range of adverse events-experiences related to the pandemic. Logistic regression was used to investigate individual-level associations (odds ratios [OR]) and population-level associations (population attributable risk proportions [PARP]) between risk factors and 30-day STB. All data were weighted using post-stratification survey weights. Results: Estimated prevalence of 30-day STB was 4.5% (1.8% active suicidal ideation; n = 5 [0.1%] suicide attempts). STB was 9.7% among the 34.3% of respondents with pre-pandemic lifetime mental disorders, and 1.8% among the 65.7% without any pre-pandemic lifetime mental disorder. Factors significantly associated with STB were pre-pandemic lifetime mental disorders (total PARP = 49.1%) and current mental disorders (total PARP = 58.4%), i.e. major depressive disorder (OR = 6.0; PARP = 39.2%), generalised anxiety disorder (OR = 5.6; PARP = 36.3%), post-traumatic stress disorder (OR = 4.6; PARP = 26.6%), panic attacks (OR = 6.7; PARP = 36.6%) and alcohol/substance use disorder (OR = 3.3; PARP = 5.9%). Pandemic-related adverse events-experiences associated with STB were lack of social support, interpersonal stress, stress about personal health and about the health of loved ones (PARPs 32.7-42.6%%), and having loved ones infected with COVID-19 (OR = 1.7; PARP = 18.8%). Up to 74.1% of STB is potentially attributable to the joint effects of mental disorders and adverse events-experiences related to the pandemic. Conclusions: STB at the end of the first wave of the Spain COVID-19 pandemic was high, and large proportions of STB are potentially attributable to mental disorders and adverse events-experiences related to the pandemic, including health-related stress, lack of social support and interpersonal stress. There is an urgent need to allocate resources to increase access to adequate mental healthcare, even in times of healthcare system overload. This study was supported by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación/FEDER (grant number COV20/00711), (PM, grant number ISCIII, CD18/00049), (grant number ISCIII, FI18/00012), (VPS, grant number PI19/00236); Ayudas para la Formación de Profesorado Universitario, Ministerio de Ciencia, Innovación y Universidades (grant number FPU15/05728); Generalitat de Catalunya (grant number 2017SGR452). The funding institutions had no role in the design, analysis, interpretation or submission of publication of the data. No payment was made for writing this article by a pharmaceutical company or other agency. Corresponding authors had full access to all the data in the study and the final responsibility for the decision of submitting for publication. Sí

Purpose Early stage Merkel cell carcinoma (MCC) is a rare and aggressive primary skin cancer. The standard of care for MCC is broad excision and adjuvant external beam radiation therapy (EBRT). However, for some patients, anesthesia is contraindicated, while others run the risk of serious aesthetic sequelae. In such cases, exclusive radiotherapy is an interesting alternative to surgery. Though limited data is available, this study evaluates exclusive radiotherapy for MCC, using data from the largest retrospective study to date. Methods All patients who were followed in our center between 1989 and 2019 for histologically proven early stage MCC were included in the study. They were treated either by surgery with a 2-cm clear margin followed by adjuvant radiotherapy (RT) or by exclusive RT. Survival rates with adjuvant and exclusive EBRT were analyzed using Cox model and Fine and Gray model depending on the type of survival. p value Results Eighty-four patients treated for MCC were included. Fifty-three of them (63.1%) were treated by exclusive RT, and 31 (36.9%) had surgical excision followed by adjuvant RT. Local relapse rate was 13.7% (95% CI 8.0–43.7) in the RT monotherapy group (group A) and 25.8% (95% CI 10.3–56.2) in the surgery + RT group (group B) (p = 0.42). No statistical difference was found for nodal relapse (p = 0.81), metastatic relapse (p = 0.10), disease free survival (p = 0.83) or overall survival (p = 0.98). Conclusion Our study suggests that exclusive radiotherapy for early Merkel cell carcinoma leads to a similar oncological outcome as combined treatment, with fewer aesthetic sequelae. The approach is interesting for elderly patients with comorbidities or patients for whom surgery would cause significant functional or aesthetic sequelae.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p

Objective Patients with melanoma and early stable disease (SD) with pembrolizumab have unclear prognosis. We present post hoc analyses of long-term outcomes for patients with early SD, partial response (PR) or complete response (CR) with pembrolizumab. Patients and methods Patients who received pembrolizumab in the KEYNOTE-001 and KEYNOTE-006 studies and had SD, PR or CR at weeks 12 or 24 were included. Results Of 294 patients in the week 12 analysis, 107 (36.4%) had SD at week 12, of whom 7 (6.5%) had a best overall response of CR, 43 (40.2%) had PR and 57 (53.3%) had SD. Forty-eight–month overall survival (OS) rates were 95.2%, 73.0% and 47.7%, respectively, for patients with CR, PR and SD at week 12. Similar results were observed in the 241 patients in the week 24 analysis. Forty-eight–month OS rates were 72.1% for patients with SD at week 12 followed by subsequent response and 75.0% for patients with PR at week 12 followed by no change in response or progression. Thirty-six–month and 48-month OS rates were 11.6% and not reached, respectively, for patients with SD at week 12 followed by progression before week 24. Conclusions A substantial proportion of patients (46.7%) with early (week 12) SD with pembrolizumab achieved subsequent PR or CR. Patients with SD at week 12 and subsequent CR/PR had similar survival to those who maintained PR. In contrast, patients with SD at week 12 and subsequent progression had poor survival outcomes. These findings may guide treatment decisions for patients achieving early SD. Trial registration Clinicaltrials.gov : NCT01295827 (KEYNOTE-001); NCT01866319 (KEYNOTE-006).

Background The COVID-19 pandemic might increase suicide behaviors. However, results are still limited and inconclusive, especially in adolescents. Methods To provide a preliminary evidence of the effects of the COVID-19 pandemic on suicide attempts (SA), we compared data from the Catalonia Suicide Risk Code (CRSC), during the first 12 months of Spain COVID-19 pandemic (March 2020 to March 2021) with data of the previous 12 months (March 2019 to March 2020). The CRSC is a well-established population-based registry of suicide attempts (SA) which allows monitoring of the dynamic changes that COVID-19 may produce in a Spanish region. Results SA among adolescents increased 25% during the COVID-year, whatever, SA among adults decreased 16,5% in the same period. The increase of SA in girls was especially prominent in the starting school period in the COVID-year (September 2020-March 2021), where the increase reached 195%. Limitations This study did not evaluate other individual risk factors of SA in the context of the COVID-19 pandemic, so is unable to make concrete causal inferences. Conclusions These finding suggest that SA increased in adolescent girls during the last period of the COVID-19 pandemic, underscoring the need to implement effective preventive measures by public health systems and stakeholders into response during this public health crisis.

International audience; Dermatofibrosarcoma protuberans (DFSP) is a soft-tissue sarcoma characterized by a high risk of local infiltration. The identification of the COL1A1-PDGFB t(17;22) translocation activating the PDGF pathway led to the use of imatinib in unresectable DFSP, with a response rate of 36-80%. Pazopanib is a multitarget tyrosine kinase inhibitor approved for soft-tissue sarcomas. We conducted a phase II study of patients with unresectable DFSP to evaluate the efficacy and safety of pazopanib. Patients received 800 mg of pazopanib daily. The primary endpoint was the objective response rate defined as the reduction of the largest diameter of the tumor by ≥30% at 6 months or at surgery. A total of 23 patients, including one pretreated with imatinib, were enrolled. With a median follow-up of 6.2 months (interquartile range = 5.6-7.8 months), five patients (22%, 95% confidence interval = 7-22%) had a partial response to pazopanib. The best objective response rate was 30% (95% confidence interval = 13-53%) using Response Evaluation Criteria in Solid Tumors. One patient with metastatic DFSP previously treated with imatinib died after 2.4 months. Nine patients (39%) discontinued the treatment owing to adverse events. Pharmacodynamics analyses of tumor samples were conducted: the enrichment of EGF and the EGFR-associated gene panel was associated with resistance, suggesting that EGFR-targeted therapies could be a therapeutic option to explore in DFSP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01059656.

Background Ipilimumab has shown long-term overall survival (OS) in patients with advanced melanoma in clinical trials, but robust real-world evidence is lacking. We present long-term outcomes from the IMAGE study (NCT01511913) in patients receiving ipilimumab and/or non-ipilimumab (any approved treatment other than ipilimumab) systemic therapies. Methods IMAGE was a multinational, prospective, observational study assessing adult patients with advanced melanoma treated with ipilimumab or non-ipilimumab systemic therapies between June 2012 and March 2015 with ≥3 years of follow-up. Adjusted OS curves based on multivariate Cox regression models included covariate effects. Safety and patient-reported outcomes were assessed. Results Among 1356 patients, 1094 (81%) received ipilimumab and 262 (19%) received non-ipilimumab index therapy (systemic therapy [chemotherapy, anti–programmed death 1 antibodies, or BRAF ± MEK inhibitors], radiotherapy, and radiosurgery). In the overall population, median age was 64 years, 60% were male, 78% were from Europe, and 78% had received previous treatment for advanced melanoma. In the ipilimumab-treated cohort, 780 (71%) patients did not receive subsequent therapy (IPI-noOther) and 314 (29%) received subsequent non-ipilimumab therapy (IPI-Other) on study. In the non-ipilimumab–treated cohort, 205 (78%) patients remained on or received other subsequent non-ipilimumab therapy (Other-Other) and 57 (22%) received subsequent ipilimumab therapy (Other-IPI) on study. Among 1151 patients who received ipilimumab at any time during the study (IPI-noOther, IPI-Other, and Other-IPI), 296 (26%) reported CTCAE grade ≥ 3 treatment-related adverse events, most occurring in year 1. Ipilimumab-treated and non-ipilimumab–treated patients who switched therapy (IPI-Other and Other-IPI) had longer OS than those who did not switch (IPI-noOther and Other-Other). Patients with prior therapy who did not switch therapy (IPI-noOther and Other-Other) showed similar OS. In treatment-naive patients, those in the IPI-noOther group tended to have longer OS than those in the Other-Other group. Patient-reported outcomes were similar between treatment cohorts. Conclusions With long-term follow-up (≥ 3 years), safety and OS in this real-world population of patients treated with ipilimumab 3 mg/kg were consistent with those reported in clinical trials. Patient-reported quality of life was maintained over the study period. OS analysis across both pretreated and treatment-naive patients suggested a beneficial role of ipilimumab early in treatment. Trial registration ClinicalTrials.gov, NCT01511913. Registered January 19, 2012 – Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01511913

With ELISAs one detects the ensemble of immunoreactive molecules in biological samples. For biomolecules undergoing proteolysis for activation, potentiation or inhibition, other techniques are necessary to study biology. Here we develop methodology that combines immunosorbent sample preparation and nano-scale liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) for proteoform analysis (ISTAMPA) and apply this to the aglycosyl chemokine CXCL8. CXCL8, the most powerful human chemokine with neutrophil chemotactic and -activating properties, occurs in different NH2-terminal proteoforms due to its susceptibility to site-specific proteolytic modification. Specific proteoforms display up to 30-fold enhanced activity. The immunosorbent ion trap top-down mass spectrometry-based approach for proteoform analysis allows for simultaneous detection and quantification of full-length CXCL8(1-77), elongated CXCL8(-2-77) and all naturally occurring truncated CXCL8 forms in biological samples. For the first time we demonstrate site-specific proteolytic activation of CXCL8 in synovial fluids from patients with chronic joint inflammation and address the importance of sample collection and processing. ispartof: FRONTIERS IN IMMUNOLOGY vol:12 ispartof: location:Switzerland status: published

International audience; Background: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups. Methods: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan–Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis. Results: Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33–8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; pMethods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.Interpretation: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting. placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting. placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.

Online alcohol screening may be helpful in preventing alcohol use disorders. We assessed psychometric properties of an online version of the Alcohol Use Disorders Identification Test (AUDIT) among Spanish university students. We used a longitudinal online survey (the UNIVERSAL project) of first-year students (18-24 years old) in five universities, including the AUDIT, as part of the WHO World Mental Health International College Student (WMH-ICS) initiative. A reappraisal interview was carried out with the Timeline Followback (TLFB) for alcohol consumption categories and the Mini International Neuropsychiatric Interview (MINI) for alcohol use disorder. Reliability, construct validity and diagnostic accuracy were assessed. Results: 287 students (75% women) completed the MINI, of whom 242 also completed the TLFB. AUDIT's Cronbach's alpha was 0.82. The confirmatory factor analysis for the one-factor solution of the AUDIT showed a good fit to the data. Significant AUDIT score differences were observed by TLFB categories and by MINI disorders. Areas under the curve (AUC) were very large for dependence (AUC = 0.96) and adequate for consumption categories (AUC > 0.7). AUDIT cut-off points of 6/8 (women/men) for moderate-risk drinking and 13 for alcohol dependence showed sensitivity/specificity of 76.2%/78.9% and 56%/97.5%, respectively. The online version of the AUDIT is useful for detecting alcohol consumption categories and alcohol dependence in Spanish university students., This research was funded by Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III FEDER (PI13/00343); Ministerio de Sanidad, Consumo y Bienestar Social, Plan Nacional Sobre Drogas PNSD (exp.2015I015); and from the DIUE of the Generalitat de Catalunya (2017SGR452). L. Ballester was supported by an FPU grant (FPU15/05728); M. J. Blasco was supported by a Rio Hortega grant (ISCIII, CM14/00125); P. Castellvi was supported by a Sara Borrell grant (ISCIII, CD12/00440), the European Regional Development Fund (ERDF), the European Commission, the University of Jaen, Spain (R08/06/2018) and the Instituto de Estudios Giennenses; and P. Mortier was supported by a Sara Borrell grant (ISCIII, CD18/00049).

[EN] Introduction: Healthcare workers are vulnerable to adverse mental health impacts of the COVID-19 pandemic. We assessed prevalence of mental disorders and associated factors during the first wave of the pandemic among healthcare professionals in Spain. Methods: All workers in 18 healthcare institutions (6 AACC) in Spain were invited to web-based surveys assessing individual characteristics, COVID-19 infection status and exposure, and mental health status (May 5 - September 7, 2020). We report: probable current mental disorders (Major Depressive Disorder-MDD- [PHQ-8≥10], Generalized Anxiety Disorder-GAD- [GAD-7≥10], Panic attacks, Posttraumatic Stress Disorder -PTSD- [PCL-5≥7]; and Substance Use Disorder -SUD-[CAGE-AID≥2]. Severe disability assessed by the Sheehan Disability Scale was used to identify probable "disabling" current mental disorders. Results: 9,138 healthcare workers participated. Prevalence of screen-positive disorder: 28.1% MDD; 22.5% GAD, 24.0% Panic; 22.2% PTSD; and 6.2% SUD. Overall 45.7% presented any current and 14.5% any disabling current mental disorder. Workers with pre-pandemic lifetime mental disorders had almost twice the prevalence than those without. Adjusting for all other variables, odds of any disabling mental disorder were: prior lifetime disorders (TUS: OR=5.74; 95%CI 2.53-13.03; Mood: OR=3.23; 95%CI:2.27-4.60; Anxiety: OR=3.03; 95%CI:2.53-3.62); age category 18-29 years (OR=1.36; 95%CI:1.02-1.82), caring "all of the time" for COVID-19 patients (OR=5.19; 95%CI: 3.61-7.46), female gender (OR=1.58; 95%CI: 1.27-1.96) and having being in quarantine or isolated (OR= 1.60; 95CI:1.31-1.95). Conclusions: One in seven Spanish healthcare workers screened positive for a disabling mental disorder during the first wave of the COVID-19 pandemic. Workers reporting pre-pandemic lifetime mental disorders, those frequently exposed to COVID-19 patients, infected or quarantined/isolated, female workers, and auxiliary nurses should be considered groups in need of mental health monitoring and support. [ES] Introducción: Los profesionales sanitarios son vulnerables al impacto negativo en salud mental de la pandemia COVID-19. Evaluamos la prevalencia de trastornos mentales y factores asociados durante la primera oleada de la pandemia en sanitarios españoles. Métodos: Se invitó a todos los trabajadores de 18 instituciones sanitarias españolas (6 CCAA) a encuestas en línea evaluando características individuales, estado de infección y exposición a COVID-19 y salud mental (5 Mayo – 7 Septiembre, 2020). Reportamos: probables trastornos mentales actuales (Trastorno depresivo mayor TDD [PHQ-8≥10], Trastorno de ansiedad generalizada TAG [GAD-7≥10], Ataques de pánico, Trastorno de estrés postraumático TEP [PCL-5≥7]; y Trastorno por uso de sustancias TUS [CAGE-AID≥2]. La interferencia funcional grave (Escala de Discapacidad de Sheehan) identificó los probables trastornos “discapacitantes”. Resultados: Participaron 9.138 sanitarios. Prevalencia de cribado positivo: 28,1% TDD; 22,5% TAG, 24,0% Pánico; 22,2% PTE; y 6,2% TUS. En general, el 45,7% presentó algún trastorno mental actual y el 14,5% algún trastorno discapacitante. Los sanitarios con trastornos mentales previos tuvieron el doble de prevalencia que aquellos sin patología mental previa. Ajustando por todas las variables, el trastorno mental incapacitante se asoció positivamente con: trastornos previos (TUS: OR=5.74; 95%CI 2.53-13.03; Ánimo: OR=3.23; 95%CI:2.27-4.60; Ansiedad: OR=3,03; IC 95%: 2,53-3,62); edad 18-29 años (OR=1,36; IC 95%: 1,02-1,82); atender “siempre” a pacientes COVID-19 (OR=5,19; IC 95%: 3,61-7,46), género femenino (OR=1,58; IC 95%: 1,27-1,96) y haber estado en cuarentena o aislado (OR=1,60; IC 95%: 1,31-1,95). Conclusiones: Uno de cada 7 sanitarios españoles presentaron un probable trastorno mental discapacitante durante la primera oleada de COVID-19. Aquéllos con trastornos mentales alguna vez antes de la pandemia, los que están expuestos con frecuencia a pacientes con COVID-19, los infectados o en cuarentena / aislados, las mujeres y las enfermeras auxiliares deben considerarse grupos que necesitan seguimiento y apoyo de su salud mental. This work was supported by Instituto de Salud Carlos III (Ministerio de Ciencia e Innovación)/FEDER (COV20/00711); ISCIII (Sara Borrell, CD18/00049) (PM); FPU (FPU15/05728)); ISCIII (PFIS, FI18/00012); Generalitat de Catalunya (2017SGR452). Sí

IntroductionHealthcare workers are vulnerable to adverse mental health impacts of COVID-19. We assessed prevalence of mental disorders and associated factors during the first wave of the pandemic among healthcare professionals in Spain.MethodsAll workers in 18 healthcare institutions (6 AACC) in Spain were invited to a series of online surveys assessing a wide range of individual characteristics, COVID-19 infection status and exposure, and mental health status. Here we report: current mental disorders (Major Depressive Disorder-MDD- [PHQ-8≥10], Generalized Anxiety Disorder-GAD- [GAD-7≥10], Panic attacks, Posttraumatic Stress Disorder –PTSD- [PCL-5≥7]; and Substance Use Disorder –SUD-[CAGE-AID≥2]. Severe disability assessed by the Sheehan Disability Scale was used to identify “disabling” current mental disorders.Results9,138 healthcare workers participated. Prevalence of screen-positive disorder: 28.1% MDD; 22.5% GAD, 24.0% Panic; 22.2% PTSD; and 6.2% SUD. Overall 45.7% presented any current and 14.5% any disabling current mental disorder. Healthcare workers with prior lifetime mental disorders had almost twice the prevalence of current disorders than those without. Adjusting for all other variables, odds of any disabling mental disorder were: prior lifetime disorders (TUS: OR=5.74; 95%CI 2.53-13.03; Mood: OR=3.23; 95%CI:2.27-4.60; Anxiety: OR=3.03; 95%CI:2.53-3.62); age category 18-29 years (OR=1.36; 95%CI:1.02-1.82), caring “all of the time” for COVID-19 patients (OR=5.19; 95%CI: 3.61-7.46), female gender (OR=1.58; 95%CI: 1.27-1.96) and having being in quarantine or isolated (OR= 1.60; 95CI:1.31-1.95).ConclusionsCurrent mental disorders were very frequent among Spanish healthcare workers during the first wave of COVID-19. As the pandemic enters its second wave, careful monitoring and support is needed for healthcare workers, especially those with previous mental disorders and those caring COVID-19 very often.

Aim: To evaluate changes in health-related quality of life (HRQoL) in a Phase II trial (NCT02155647) of treatment-naive patients with metastatic Merkel cell carcinoma treated with avelumab (15-month follow-up). Materials & methods: Mixed-effect Models for Repeated Measures were applied to HRQoL data (FACT-M; EQ-5D-5L) to assess changes over time. Clinically derived progression-free survival was compared with HRQoL deterioration-free survival. Results: Overall, we saw relative stability in HRQoL among 116 included patients, with nonprogression associated with statistically and clinically meaningful better HRQoL compared with progressive disease. Deterioration-free survival rates (49–72% at 6 months, 40–58% at 12 months) were consistently higher/better compared with progression-free survival rates (41/31% at 6/12 months). Conclusion: These findings show unique longitudinal HRQoL data for treatment-naive metastatic Merkel cell carcinoma patients treated with avelumab. Clinical trial registration: NCT02155647 ( ClinicalTrials.gov ).